SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

Rubén Fernández-Santiago; Núria Martín-Flores; Francesca Antonelli; Catalina Cerquera; Verónica Moreno; Sara Bandres-Ciga; Elisabetta Manduchi; Eduard Tolosa; Andrew B. Singleton; Jason H. Moore; María Josep Martí; Mario Ezquerra; Cristina Malagelada; Alastair J. Noyce; Rauan Kaiyrzhanov; Ben Middlehurst; Demis A. Kia; Manuela Tan; Henry Houlden; Huw R. Morris; Helene Plun-Favreau; Peter Holmans; John Hardy; Daniah Trabzuni; Jose Bras; John Quinn; Kin Y. Mok; Kerri J. Kinghorn; Kimberley Billingsley; Nicholas W. Wood; Patrick Lewis; Sebastian Schreglmann; Rita Guerreiro; Ruth Lovering; Lea R’Bibo; Claudia Manzoni; Mie Rizig; Mina Ryten; Sebastian Guelfi; Valentina Escott-Price; Viorica Chelban; Thomas Foltynie; Nigel Williams; Karen E. Morrison; Carl Clarke; Alexis Brice; Fabrice Danjou; Suzanne Lesage; Jean Christophe Corvol; Maria Martinez; Claudia Schulte; Kathrin Brockmann; Javier Simon-Sanchez; Peter Heutink; Patrizia Rizzu; Manu Sharma; Thomas Gasser; Aude Nicolas; Mark R. Cookson; Cornelis Blauwendraat; David W. Craig; Faraz Faghri; J. Raphael Gibbs; Dena G. Hernandez; Kendall Van Keuren-Jensen; Joshua M. Shulman; Hirotaka Iwaki; Hampton L. Leonard; Mike A. Nalls; Laurie Robak; Steven Lubbe; Steven Finkbeiner; Niccolo E. Mencacci; Codrin Lungu; Sonja W. Scholz; Xylena Reed; Roy N. Alcalay; Ziv Gan-Or; Guy A. Rouleau; Lynne Krohn; Jacobus J. Van Hilten; Johan Marinus; Astrid D. Adarmes-Gómez; Iquel Aguilar; Ignacio Alvarez; Victoria Alvarez; Francisco Javier Barrero; Jesús Alberto Bergareche Yarza; Inmaculada Bernal-Bernal; Marta Blazquez; Marta Bonilla-Toribio; Juan A. Botía; María Teresa Boungiorno; Dolores Buiza-Rueda; Ana Cámara; Fátima Carrillo; Mario Carrión-Claro; Debora Cerdan; Jordi Clarimón; Yaroslau Compta; Beatriz De La Casa; Monica Diez-Fairen; Oriol Dols-Icardo; Jacinto Duarte; Raquel Duran; Francisco Escamilla-Sevilla; Cici Feliz; Manel Fernández; Ciara Garcia; Pedro García-Ruiz; Pilar Gómez-Garre; Maria Jose Gomez Heredia; Isabel Gonzalez-Aramburu; Ana Gorostidi Pagola; Janet Hoenicka; Jon Infante; Silvia Jesús; Adriano Jimenez-Escrig; Jaime Kulisevsky; Miguel A. Labrador-Espinosa; Jose Luis Lopez-Sendon; Adolfo López De Munainarregui; Daniel Macias; Irene Martínez Torres; Juan Marín; Maria Jose Marti; Juan Carlos Mar-Tínez-castrillo; Carlota Méndez-Del-barrio; Manuel Menéndez González; Marina Mata; Adolfo Mínguez; Pablo Mir; Elisabet Mondragon Rezola; Esteban Muñoz; Javier Pagonabarraga; Berta Pascual-Sedano; Pau Pastor; Francisco Perez Errazquin; Teresa Periñán-Tocino; Javier Ruiz-Martínez; Clara Ruz; Antonio Sanchez Rodriguez; María Sierra; Esther Suarez-Sanmartin; Cesar Tabernero; Juan Pablo Tartari; Cristina Tejera-Parrado; Francesc Valldeoriola; Laura Vargas-González; Lydia Vela; Francisco Vives; Alexander Zimprich; Lasse Pihlstrom; Mathias Toft; Sulev Koks; Pille Taba; Sharon Hassin-Baer

doi:10.1002/mds.27770

SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

Rubén Fernández-Santiago, Núria Martín-Flores, Francesca Antonelli, Catalina Cerquera, Verónica Moreno, Sara Bandres-Ciga, Elisabetta Manduchi, Eduard Tolosa, Andrew B. Singleton, Jason H. Moore, María Josep Martí, Mario Ezquerra, Cristina Malagelada^*, Alastair J. Noyce, Rauan Kaiyrzhanov, Ben Middlehurst, Demis A. Kia, Manuela Tan, Henry Houlden, Huw R. MorrisHelene Plun-Favreau, Peter Holmans, John Hardy, Daniah Trabzuni, Jose Bras, John Quinn, Kin Y. Mok, Kerri J. Kinghorn, Kimberley Billingsley, Nicholas W. Wood, Patrick Lewis, Sebastian Schreglmann, Rita Guerreiro, Ruth Lovering, Lea R’Bibo, Claudia Manzoni, Mie Rizig, Mina Ryten, Sebastian Guelfi, Valentina Escott-Price, Viorica Chelban, Thomas Foltynie, Nigel Williams, Karen E. Morrison, Carl Clarke, Alexis Brice, Fabrice Danjou, Suzanne Lesage, Jean Christophe Corvol, Maria Martinez, Claudia Schulte, Kathrin Brockmann, Javier Simon-Sanchez, Peter Heutink, Patrizia Rizzu, Manu Sharma, Thomas Gasser, Aude Nicolas, Mark R. Cookson, Cornelis Blauwendraat, David W. Craig, Faraz Faghri, J. Raphael Gibbs, Dena G. Hernandez, Kendall Van Keuren-Jensen, Joshua M. Shulman, Hirotaka Iwaki, Hampton L. Leonard, Mike A. Nalls, Laurie Robak, Steven Lubbe, Steven Finkbeiner, Niccolo E. Mencacci, Codrin Lungu, Sonja W. Scholz, Xylena Reed, Roy N. Alcalay, Ziv Gan-Or, Guy A. Rouleau, Lynne Krohn, Jacobus J. Van Hilten, Johan Marinus, Astrid D. Adarmes-Gómez, Iquel Aguilar, Ignacio Alvarez, Victoria Alvarez, Francisco Javier Barrero, Jesús Alberto Bergareche Yarza, Inmaculada Bernal-Bernal, Marta Blazquez, Marta Bonilla-Toribio, Juan A. Botía, María Teresa Boungiorno, Dolores Buiza-Rueda, Ana Cámara, Fátima Carrillo, Mario Carrión-Claro, Debora Cerdan, Jordi Clarimón, Yaroslau Compta, Beatriz De La Casa, Monica Diez-Fairen, Oriol Dols-Icardo, Jacinto Duarte, Raquel Duran, Francisco Escamilla-Sevilla, Cici Feliz, Manel Fernández, Ciara Garcia, Pedro García-Ruiz, Pilar Gómez-Garre, Maria Jose Gomez Heredia, Isabel Gonzalez-Aramburu, Ana Gorostidi Pagola, Janet Hoenicka, Jon Infante, Silvia Jesús, Adriano Jimenez-Escrig, Jaime Kulisevsky, Miguel A. Labrador-Espinosa, Jose Luis Lopez-Sendon, Adolfo López De Munainarregui, Daniel Macias, Irene Martínez Torres, Juan Marín, Maria Jose Marti, Juan Carlos Mar-Tínez-castrillo, Carlota Méndez-Del-barrio, Manuel Menéndez González, Marina Mata, Adolfo Mínguez, Pablo Mir, Elisabet Mondragon Rezola, Esteban Muñoz, Javier Pagonabarraga, Berta Pascual-Sedano, Pau Pastor, Francisco Perez Errazquin, Teresa Periñán-Tocino, Javier Ruiz-Martínez, Clara Ruz, Antonio Sanchez Rodriguez, María Sierra, Esther Suarez-Sanmartin, Cesar Tabernero, Juan Pablo Tartari, Cristina Tejera-Parrado, Francesc Valldeoriola, Laura Vargas-González, Lydia Vela, Francisco Vives, Alexander Zimprich, Lasse Pihlstrom, Mathias Toft, Sulev Koks, Pille Taba, Sharon Hassin-Baer

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Background: Single nucleotide polymorphisms (SNPs) in the α-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. Objectives: The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. Methods: Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. Results: In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P <.001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P <.0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. Conclusions: These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease.

Original language	English
Pages (from-to)	1333-1344
Number of pages	12
Journal	Movement Disorders
Volume	34
Issue number	9
DOIs	https://doi.org/10.1002/mds.27770
State	Published - 1 Sep 2019

Funding

Funders	Funder number
AEI/FEDER/UE
FEDER Agencia Europea de Investigacion/Fondo Europeo de Desarrollo Regional/Union Europea
ICDCI
National Institute on Aging	ZIAAG000949
Universitat Pompeu Fabra
European Commission	SAF2015-73508-JIN
Generalitat de Catalunya
Ministerio de Economía y Competitividad
European Regional Development Fund
Agencia Estatal de Investigación

Keywords

Parkinson's disease
SNP
age at onset
alpha-synuclein
epistasis
mTOR

Access to Document

10.1002/mds.27770

Cite this

Fernández-Santiago, R., Martín-Flores, N., Antonelli, F., Cerquera, C., Moreno, V., Bandres-Ciga, S., Manduchi, E., Tolosa, E., Singleton, A. B., Moore, J. H., Martí, M. J., Ezquerra, M., Malagelada, C., Noyce, A. J., Kaiyrzhanov, R., Middlehurst, B., Kia, D. A., Tan, M., Houlden, H., ... Hassin-Baer, S. (2019). SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease. Movement Disorders, 34(9), 1333-1344. https://doi.org/10.1002/mds.27770

@article{ff75f72a83784490bedf133f235ade97,

title = "SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease",

abstract = "Background: Single nucleotide polymorphisms (SNPs) in the α-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. Objectives: The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. Methods: Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. Results: In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P <.001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P <.0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. Conclusions: These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease.",

keywords = "Parkinson's disease, SNP, age at onset, alpha-synuclein, epistasis, mTOR",

author = "Rub{\'e}n Fern{\'a}ndez-Santiago and N{\'u}ria Mart{\'i}n-Flores and Francesca Antonelli and Catalina Cerquera and Ver{\'o}nica Moreno and Sara Bandres-Ciga and Elisabetta Manduchi and Eduard Tolosa and Singleton, {Andrew B.} and Moore, {Jason H.} and Mart{\'i}, {Mar{\'i}a Josep} and Mario Ezquerra and Cristina Malagelada and Noyce, {Alastair J.} and Rauan Kaiyrzhanov and Ben Middlehurst and Kia, {Demis A.} and Manuela Tan and Henry Houlden and Morris, {Huw R.} and Helene Plun-Favreau and Peter Holmans and John Hardy and Daniah Trabzuni and Jose Bras and John Quinn and Mok, {Kin Y.} and Kinghorn, {Kerri J.} and Kimberley Billingsley and Wood, {Nicholas W.} and Patrick Lewis and Sebastian Schreglmann and Rita Guerreiro and Ruth Lovering and Lea R{\textquoteright}Bibo and Claudia Manzoni and Mie Rizig and Mina Ryten and Sebastian Guelfi and Valentina Escott-Price and Viorica Chelban and Thomas Foltynie and Nigel Williams and Morrison, {Karen E.} and Carl Clarke and Alexis Brice and Fabrice Danjou and Suzanne Lesage and Corvol, {Jean Christophe} and Maria Martinez and Claudia Schulte and Kathrin Brockmann and Javier Simon-Sanchez and Peter Heutink and Patrizia Rizzu and Manu Sharma and Thomas Gasser and Aude Nicolas and Cookson, {Mark R.} and Cornelis Blauwendraat and Craig, {David W.} and Faraz Faghri and Gibbs, {J. Raphael} and Hernandez, {Dena G.} and {Van Keuren-Jensen}, Kendall and Shulman, {Joshua M.} and Hirotaka Iwaki and Leonard, {Hampton L.} and Nalls, {Mike A.} and Laurie Robak and Steven Lubbe and Steven Finkbeiner and Mencacci, {Niccolo E.} and Codrin Lungu and Scholz, {Sonja W.} and Xylena Reed and Alcalay, {Roy N.} and Ziv Gan-Or and Rouleau, {Guy A.} and Lynne Krohn and {Van Hilten}, {Jacobus J.} and Johan Marinus and Adarmes-G{\'o}mez, {Astrid D.} and Iquel Aguilar and Ignacio Alvarez and Victoria Alvarez and Barrero, {Francisco Javier} and {Bergareche Yarza}, {Jes{\'u}s Alberto} and Inmaculada Bernal-Bernal and Marta Blazquez and Marta Bonilla-Toribio and Bot{\'i}a, {Juan A.} and Boungiorno, {Mar{\'i}a Teresa} and Dolores Buiza-Rueda and Ana C{\'a}mara and F{\'a}tima Carrillo and Mario Carri{\'o}n-Claro and Debora Cerdan and Jordi Clarim{\'o}n and Yaroslau Compta and {De La Casa}, Beatriz and Monica Diez-Fairen and Oriol Dols-Icardo and Jacinto Duarte and Raquel Duran and Francisco Escamilla-Sevilla and Cici Feliz and Manel Fern{\'a}ndez and Ciara Garcia and Pedro Garc{\'i}a-Ruiz and Pilar G{\'o}mez-Garre and {Gomez Heredia}, {Maria Jose} and Isabel Gonzalez-Aramburu and Pagola, {Ana Gorostidi} and Janet Hoenicka and Jon Infante and Silvia Jes{\'u}s and Adriano Jimenez-Escrig and Jaime Kulisevsky and Labrador-Espinosa, {Miguel A.} and Lopez-Sendon, {Jose Luis} and {De Munainarregui}, {Adolfo L{\'o}pez} and Daniel Macias and Torres, {Irene Mart{\'i}nez} and Juan Mar{\'i}n and Marti, {Maria Jose} and Mar-T{\'i}nez-castrillo, {Juan Carlos} and Carlota M{\'e}ndez-Del-barrio and Gonz{\'a}lez, {Manuel Men{\'e}ndez} and Marina Mata and Adolfo M{\'i}nguez and Pablo Mir and Rezola, {Elisabet Mondragon} and Esteban Mu{\~n}oz and Javier Pagonabarraga and Berta Pascual-Sedano and Pau Pastor and Errazquin, {Francisco Perez} and Teresa Peri{\~n}{\'a}n-Tocino and Javier Ruiz-Mart{\'i}nez and Clara Ruz and Rodriguez, {Antonio Sanchez} and Mar{\'i}a Sierra and Esther Suarez-Sanmartin and Cesar Tabernero and Tartari, {Juan Pablo} and Cristina Tejera-Parrado and Francesc Valldeoriola and Laura Vargas-Gonz{\'a}lez and Lydia Vela and Francisco Vives and Alexander Zimprich and Lasse Pihlstrom and Mathias Toft and Sulev Koks and Pille Taba and Sharon Hassin-Baer",

note = "Publisher Copyright: {\textcopyright} 2019 International Parkinson and Movement Disorder Society",

year = "2019",

month = sep,

day = "1",

doi = "10.1002/mds.27770",

language = "אנגלית",

volume = "34",

pages = "1333--1344",

journal = "Movement Disorders",

issn = "0885-3185",

publisher = "John Wiley & Sons Inc.",

number = "9",

}

Fernández-Santiago, R, Martín-Flores, N, Antonelli, F, Cerquera, C, Moreno, V, Bandres-Ciga, S, Manduchi, E, Tolosa, E, Singleton, AB, Moore, JH, Martí, MJ, Ezquerra, M, Malagelada, C, Noyce, AJ, Kaiyrzhanov, R, Middlehurst, B, Kia, DA, Tan, M, Houlden, H, Morris, HR, Plun-Favreau, H, Holmans, P, Hardy, J, Trabzuni, D, Bras, J, Quinn, J, Mok, KY, Kinghorn, KJ, Billingsley, K, Wood, NW, Lewis, P, Schreglmann, S, Guerreiro, R, Lovering, R, R’Bibo, L, Manzoni, C, Rizig, M, Ryten, M, Guelfi, S, Escott-Price, V, Chelban, V, Foltynie, T, Williams, N, Morrison, KE, Clarke, C, Brice, A, Danjou, F, Lesage, S, Corvol, JC, Martinez, M, Schulte, C, Brockmann, K, Simon-Sanchez, J, Heutink, P, Rizzu, P, Sharma, M, Gasser, T, Nicolas, A, Cookson, MR, Blauwendraat, C, Craig, DW, Faghri, F, Gibbs, JR, Hernandez, DG, Van Keuren-Jensen, K, Shulman, JM, Iwaki, H, Leonard, HL, Nalls, MA, Robak, L, Lubbe, S, Finkbeiner, S, Mencacci, NE, Lungu, C, Scholz, SW, Reed, X, Alcalay, RN, Gan-Or, Z, Rouleau, GA, Krohn, L, Van Hilten, JJ, Marinus, J, Adarmes-Gómez, AD, Aguilar, I, Alvarez, I, Alvarez, V, Barrero, FJ, Bergareche Yarza, JA, Bernal-Bernal, I, Blazquez, M, Bonilla-Toribio, M, Botía, JA, Boungiorno, MT, Buiza-Rueda, D, Cámara, A, Carrillo, F, Carrión-Claro, M, Cerdan, D, Clarimón, J, Compta, Y, De La Casa, B, Diez-Fairen, M, Dols-Icardo, O, Duarte, J, Duran, R, Escamilla-Sevilla, F, Feliz, C, Fernández, M, Garcia, C, García-Ruiz, P, Gómez-Garre, P, Gomez Heredia, MJ, Gonzalez-Aramburu, I, Pagola, AG, Hoenicka, J, Infante, J, Jesús, S, Jimenez-Escrig, A, Kulisevsky, J, Labrador-Espinosa, MA, Lopez-Sendon, JL, De Munainarregui, AL, Macias, D, Torres, IM, Marín, J, Marti, MJ, Mar-Tínez-castrillo, JC, Méndez-Del-barrio, C, González, MM, Mata, M, Mínguez, A, Mir, P, Rezola, EM, Muñoz, E, Pagonabarraga, J, Pascual-Sedano, B, Pastor, P, Errazquin, FP, Periñán-Tocino, T, Ruiz-Martínez, J, Ruz, C, Rodriguez, AS, Sierra, M, Suarez-Sanmartin, E, Tabernero, C, Tartari, JP, Tejera-Parrado, C, Valldeoriola, F, Vargas-González, L, Vela, L, Vives, F, Zimprich, A, Pihlstrom, L, Toft, M, Koks, S, Taba, P & Hassin-Baer, S 2019, 'SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease', Movement Disorders, vol. 34, no. 9, pp. 1333-1344. https://doi.org/10.1002/mds.27770

TY - JOUR

T1 - SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

AU - Fernández-Santiago, Rubén

AU - Martín-Flores, Núria

AU - Antonelli, Francesca

AU - Cerquera, Catalina

AU - Moreno, Verónica

AU - Bandres-Ciga, Sara

AU - Manduchi, Elisabetta

AU - Tolosa, Eduard

AU - Singleton, Andrew B.

AU - Moore, Jason H.

AU - Martí, María Josep

AU - Ezquerra, Mario

AU - Malagelada, Cristina

AU - Noyce, Alastair J.

AU - Kaiyrzhanov, Rauan

AU - Middlehurst, Ben

AU - Kia, Demis A.

AU - Tan, Manuela

AU - Houlden, Henry

AU - Morris, Huw R.

AU - Plun-Favreau, Helene

AU - Holmans, Peter

AU - Hardy, John

AU - Trabzuni, Daniah

AU - Bras, Jose

AU - Quinn, John

AU - Mok, Kin Y.

AU - Kinghorn, Kerri J.

AU - Billingsley, Kimberley

AU - Wood, Nicholas W.

AU - Lewis, Patrick

AU - Schreglmann, Sebastian

AU - Guerreiro, Rita

AU - Lovering, Ruth

AU - R’Bibo, Lea

AU - Manzoni, Claudia

AU - Rizig, Mie

AU - Ryten, Mina

AU - Guelfi, Sebastian

AU - Escott-Price, Valentina

AU - Chelban, Viorica

AU - Foltynie, Thomas

AU - Williams, Nigel

AU - Morrison, Karen E.

AU - Clarke, Carl

AU - Brice, Alexis

AU - Danjou, Fabrice

AU - Lesage, Suzanne

AU - Corvol, Jean Christophe

AU - Martinez, Maria

AU - Schulte, Claudia

AU - Brockmann, Kathrin

AU - Simon-Sanchez, Javier

AU - Heutink, Peter

AU - Rizzu, Patrizia

AU - Sharma, Manu

AU - Gasser, Thomas

AU - Nicolas, Aude

AU - Cookson, Mark R.

AU - Blauwendraat, Cornelis

AU - Craig, David W.

AU - Faghri, Faraz

AU - Gibbs, J. Raphael

AU - Hernandez, Dena G.

AU - Van Keuren-Jensen, Kendall

AU - Shulman, Joshua M.

AU - Iwaki, Hirotaka

AU - Leonard, Hampton L.

AU - Nalls, Mike A.

AU - Robak, Laurie

AU - Lubbe, Steven

AU - Finkbeiner, Steven

AU - Mencacci, Niccolo E.

AU - Lungu, Codrin

AU - Scholz, Sonja W.

AU - Reed, Xylena

AU - Alcalay, Roy N.

AU - Gan-Or, Ziv

AU - Rouleau, Guy A.

AU - Krohn, Lynne

AU - Van Hilten, Jacobus J.

AU - Marinus, Johan

AU - Adarmes-Gómez, Astrid D.

AU - Aguilar, Iquel

AU - Alvarez, Ignacio

AU - Alvarez, Victoria

AU - Barrero, Francisco Javier

AU - Bergareche Yarza, Jesús Alberto

AU - Bernal-Bernal, Inmaculada

AU - Blazquez, Marta

AU - Bonilla-Toribio, Marta

AU - Botía, Juan A.

AU - Boungiorno, María Teresa

AU - Buiza-Rueda, Dolores

AU - Cámara, Ana

AU - Carrillo, Fátima

AU - Carrión-Claro, Mario

AU - Cerdan, Debora

AU - Clarimón, Jordi

AU - Compta, Yaroslau

AU - De La Casa, Beatriz

AU - Diez-Fairen, Monica

AU - Dols-Icardo, Oriol

AU - Duarte, Jacinto

AU - Duran, Raquel

AU - Escamilla-Sevilla, Francisco

AU - Feliz, Cici

AU - Fernández, Manel

AU - Garcia, Ciara

AU - García-Ruiz, Pedro

AU - Gómez-Garre, Pilar

AU - Gomez Heredia, Maria Jose

AU - Gonzalez-Aramburu, Isabel

AU - Pagola, Ana Gorostidi

AU - Hoenicka, Janet

AU - Infante, Jon

AU - Jesús, Silvia

AU - Jimenez-Escrig, Adriano

AU - Kulisevsky, Jaime

AU - Labrador-Espinosa, Miguel A.

AU - Lopez-Sendon, Jose Luis

AU - De Munainarregui, Adolfo López

AU - Macias, Daniel

AU - Torres, Irene Martínez

AU - Marín, Juan

AU - Marti, Maria Jose

AU - Mar-Tínez-castrillo, Juan Carlos

AU - Méndez-Del-barrio, Carlota

AU - González, Manuel Menéndez

AU - Mata, Marina

AU - Mínguez, Adolfo

AU - Mir, Pablo

AU - Rezola, Elisabet Mondragon

AU - Muñoz, Esteban

AU - Pagonabarraga, Javier

AU - Pascual-Sedano, Berta

AU - Pastor, Pau

AU - Errazquin, Francisco Perez

AU - Periñán-Tocino, Teresa

AU - Ruiz-Martínez, Javier

AU - Ruz, Clara

AU - Rodriguez, Antonio Sanchez

AU - Sierra, María

AU - Suarez-Sanmartin, Esther

AU - Tabernero, Cesar

AU - Tartari, Juan Pablo

AU - Tejera-Parrado, Cristina

AU - Valldeoriola, Francesc

AU - Vargas-González, Laura

AU - Vela, Lydia

AU - Vives, Francisco

AU - Zimprich, Alexander

AU - Pihlstrom, Lasse

AU - Toft, Mathias

AU - Koks, Sulev

AU - Taba, Pille

AU - Hassin-Baer, Sharon

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Background: Single nucleotide polymorphisms (SNPs) in the α-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. Objectives: The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. Methods: Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. Results: In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P <.001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P <.0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. Conclusions: These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease.

AB - Background: Single nucleotide polymorphisms (SNPs) in the α-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. Objectives: The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. Methods: Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. Results: In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P <.001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P <.0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. Conclusions: These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease.

KW - Parkinson's disease

KW - SNP

KW - age at onset

KW - alpha-synuclein

KW - epistasis

KW - mTOR

UR - http://www.scopus.com/inward/record.url?scp=85068083474&partnerID=8YFLogxK

U2 - 10.1002/mds.27770

DO - 10.1002/mds.27770

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 31234232

AN - SCOPUS:85068083474

SN - 0885-3185

VL - 34

SP - 1333

EP - 1344

JO - Movement Disorders

JF - Movement Disorders

IS - 9

ER -

SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

Abstract

Funding

Keywords

Access to Document

Other files and links

Fingerprint

Cite this